1. Field of the Invention
The present invention relates to processes for manufacturing glutamic acid derivatives and pyroglutamic acid derivatives, in particular monatin, and novel intermediates used in the manufacture thereof by that process.
2. Discussion of the Background
Specific glutamic acid derivatives, including monatin as a typical example, are compounds expected to be useful as sweeteners, or intermediates in the manufacture of drugs, etc. Monatin is a naturally occurring amino acid derivative isolated from the bark of the root of Schlerochiton ilicifolius, a plant growing naturally in the northern Transvaal area of South Africa and its structure has been reported by R. Vleggaar et al as being of (2S,4S)-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl) pentanoic acid ((2S,4S)-4-hydroxy-4-(3-indolyl-methyl)-glutamic acid; see formula (19) below) (see R. Vleggaar et al, J. Chem. Soc. Perkin Trans., pp. 3095-3098 (1992)).
The same literature reports that the (2S, 4S) form of monatin reportedly obtainable from a natural plant has a sweetness (or sweetness intensity) which is 800 or 1,400 times that of sucrose. Several methods have been reported as methods of synthesizing monatin, but to date there has not been any industrially suitable method (for examples of synthesis, reference is made to Republic of South Africa Patent Application No. 87/4288 (P. J. van Wyk et al, ZA87/4288); C. W. Holzapfel et al, Synthetic Communications, vol. 24(22), pp. 3197-3211 (1994); U.S. Pat. No. 5,994,559; and K. Nakamura et al, Organic Letters, vol. 2, pp. 2967-2970 (2000), etc.).
D. J. Oliveira et al (see, Tetrahedron Letters, vol. 42, pp. 6793-6796 (2001)) have reported that a monatin derivative having a protective group as shown by formula (17) below can be synthesized stereoselectively by alkylating a lactam derivative as shown by formula (16) below and subjecting it to hydrolysis and an oxidizing reaction.
(where TBDMS stands for a t-butyldimethylsilyl group, Cbz stands for a benzyloxycarbonyl group, tBoc stands for a t-butoxycarbonyl group and Et stands for an ethyl group.)
(where tBoc is as defined above.)
However, this method involves complicated procedures including reducing the carboxyl group of a pyroglutamic acid derivative into a hydroxymethyl group, converting it to a protected hydroxymethyl group and introducing a hydroxyl group into the 4-position for the preparation of compound (16), and after the alkylation of compound (16), conducting the deprotection of the protected hydroxymethyl group into a hydroxymethyl group and oxidizing it back into a carboxyl group, though the compound represented by formula (16) is capable of regioselective alkylation as it has only a single active hydrogen atom.
Chromium trioxide (CrO3) is used in the oxidizing reaction, but the reaction using it presents a great many problems as a method of manufacture, since this reagent is dangerous because of toxicity, etc. Moreover, it is not desirable for any process of manufacture to include any oxidizing reaction of any compound having an indole ring, since the indole ring is easily oxidizable.
As regards the alkylation at the 4-position of a pyroglutamic acid derivative having a carboxyl group which is not reduced, which differs from the above case, J. Ezquerra et al (see, J. Org. Chem., vol. 59, pp. 4327-4331 (1994)) have, for example, reported a method of producing a 4,4-dialkylpyroglutamic acid derivative by dialkylating the 4-position of a pyroglutamic acid derivative represented by formula (18) below.
(where tBoc and Et are as defined above.)
However, there has not been reported any case of the selective alkylation at the 4-position of a pyroglutamic acid derivative having a protected hydroxyl group at the 4-position and having a carboxyl group which is reduced like a compound represented by formula (1) below.
Thus, there remains a need for processes for manufacturing glutamic acid derivatives and pyroglutamic acid derivatives, in particular monatin, and novel intermediates used in the manufacture thereof by that process.